2,4-diamino quinazoline derivatives

ABSTRACT

Compounds having the structure shown in FIG. 1 where Y is S, SO or SO2, and Ar is p-chlorophenyl, Alpha , Alpha , Alpha trifluoro-m-tolyl or 2-naphthyl. Specific compounds disclosed are: 2,4-diamino-6-((p-chlorophenyl)thio) quinazoline (FIG. 2); 2,4-diamino-6-(( Alpha , Alpha , Alpha -trifluoro-mtolyl)thio)quinazoline (FIG. 3); 2,4-diamino-6-(2-naphthylthio) quinazoline (FIG. 4); 2,4-diamino-6-(-naphthylsulfinyl)quinazoline (FIG. 5); (FIG. 6). These compounds are useful for antimalarial and antibacterial purposes. The thio compounds are synthesized according to the following process: And the sulfinyl and sulfonyl compounds are synthesized according to this process:

United States Patent [191 Elslager et al.

[ 2,4-DIAMINO QUINAZOLINE DERIVATIVES [75] Inventors: Edward F.Elslager; Leslie M.

Werbel, both of Ann Arbor, Mich.

[73] Assignee: The United States of America as represented by theSecretary of the Army, Washington, DC.

[22] Filed: Jan. 17, 1973 [21] Appl. No.: 324,276

[30] Foreign Application Priority Data Apr. 7, 1972 Great Britain16230/72 [52] US. Cl.... 260/256.5 R, 260/465 R, 260/465 F,

' Y 424/251 [51] Int. Cl.... C07d 51/48 [58] Field of Search 260/256.5 R

[56] References Cited UNITED STATES PATENTS 2.953.567 9/l960 Hitchingset al. 260/256.5 R 3.635979 l/l972 OTHER PUBLICATIONS FALCO et al.,Chem. Abstracts, 46:4675 b, (1949).

Primary Examiner-Richard J. Gallagher Attorney, Agenl, 0r Firm-James E.Noble; William G. Gapcynski; Lawrence A. Neureither [57] ABSTRACTCompounds having the structure'shown in Fig. 1 where Y is S, S0 or S0and Ar is p-chlorophenyl, a, a, a-trifluoro-m-tolyl or Z-naphthyl.Specific com- Hess 260/256.5 R

[111 3,853,873 45] Dec. 10,1974

And the sulfinyl and sulfonyl compounds are synthesized according tothis process:

6 Claims, 7 Drawing Figures PATENTEL M 3.853.873

SHEET 1 2.

Cl 8 Y I v NH PATENTEL I 3.853.873

' sum 2 or 2 FIG.4

1 2,4- DIA MINQ QUINAZOL INE DERIVATIVES The invention herein describedwas made in the course of, or under, a contract, or subcontractthereunder, with the Department of the Army.

BACKGROUND OF INVENTION 1. Field of the Invention This invention relatesto 2,4-diamino-6-[(arylthio) substituted]quinazoline compounds, and theuse of compounds of this type for antibacterial purposes andantimalarial purposes.

2. Description of the Prior Art The prior art includes the compound2,4-diamino-6- (3,4-dichlorobenzylamino)quinazoline which has thestructure shown in FIG. 7. This prior art compound is disclosed inBritish Pat. No. 1,045,180 (Oct. 12, 1966) (inventor: I. Davoll) and useof the compound as an antimalarial chemotherapeutic agent is taught byThompson et al., Experimental Parasitology, 25: 32-49 (1969). This priorart compound is sometimes designated as PAM 1392.

The Thompson et al. publication, above, states on p.

47: The approximate potency of the drug [PAM 1392] relative to quinineon a weight basis was deter mined in mice under several test conditions.These studies indicated PAM 1392 to have the following orders of greateractivity than quinine: 6- to 9-fold with drug-diet treatment, 4-foldwith eight doses by gavage, and 1 l-fold with eight subcutaneous doses."

The novel compounds of the instant invention have some structuralsimilarity to PAM 1392. However, what is completely unexpectedconcerning the novel compounds of the instant invention is that theyhave antimalarial activity which vastly exceeds that of PAM 1392.Whereas the prior art teaches that PAM 1392 has a quinine equivalent onthe order of 4 to l 1, de-

pending on theparticular mode of administration, the compounds of thisinvention have quinine equivalents on the order of 300 to 800. This fargreater activity from structurally similar compounds is unexpected andunpredictable to a person of ordinary skill in the art.

SUMMARY OF THE INVENTION This invention comprises the creation of newcompounds having the general formula shown in FIG. 1 wherein Y is S, S0,or S and Ar is 4-chlorophenyl, a,a,a-trifluoro-m-tolyl, or Z-naphthyl.specific compounds invented include the following: 2,4-diamino-6-[(p-chlorophenyl)thio]quinazoline (FIG. 2); 2,4- diamino-6[a,a,a-trifluoro-m-tolyl)thio]quinazoline (FIG. 3); 2,4-diamino-6-(Z-naphthylthio )quinazoline (FIG. 4);2,4-diamino-6-(2-naphthylsulfinyl)quinazoline (FIG. 5); and2,4-diamino-6-(2-naphthylsulfonyl)- quinazoline (FIG. 6). Thesecompounds are highly active antimalarial and antibacterial agents.

Accordingly, another aspect of this invention comprises providing newprocesses for the prevention and treatment of malaria in mammals andnew'processes' for the prevention and treatment of bacterial infections.Whenever the term mammals is used in the specification and claims itshould be understood as including humans.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is the structural fonnula forthe compounds of this invention wherein Y is S, S0 or S0 and Ar is p-DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of this inventionmay be prepared by the processes described above in the Abstract of theDisclosure. Specific examples showing the preparation of each compoundwill now be given. All temperatures are given in degrees Celsius (C) andmetric units are employed for weights and measures.

EXAMPLE I Preparation of2,4-Diamino-6-[(p-chlorophenyl)thio]-quinazoline, one-third Hydrate2-Nitro5- p-c hlorophenyl )thio]benzonitrile was prepared fromp-chlorobenzenethiol, potassium carbonate and5-chloro-2-nitrobenzonitrile. Reduction with stannous chloride afforded2-amino-5-[(pchlorophenyl)thio]benzonitrile which was condensed withchloroformamidine hydrochloride (see A. Hantzsch and A. Vagt, Ann., 314,366 (1900)) to give the end-product compound having the structure shownin FIG. 2.

2-Nitro-5-[(p-chlorophenyl)thio]benzonitrile A mixture of 6.4 g (0.044mole) of pchlorobenzenethiol, 8.0 g (0.044 mole) of 5-chloro-2-nitrobenzonitrile and 6.7 g (0.048 mole) of potassium carbonate in 120ml acetone was heated under reflux for 3 hr. The salt present wasremoved by filtration and the solvent was removed from the filtrateunder reduced pressure. The oily residue was dissolved in hot ethanoland allowed to cool. The yellow solid obtained was recrystallized fromacetonitrile to give 6.2 g (49%) of the desired product, mp 107-109.

Anal. Calcd for C,;,H ClN- O S: C. 53.70; H. 2.43; N, 9.

Found: C. 53.65; H. 2.50; N, 9.63.

2-Amino-5-[(p-chlorophenyl)thio]benzonitrile To astirred solution of 18g (0.08 mole) of stannous chloride dihydrate in a mixture of 60 ml ofconcentrated hydrochloric acid and 10 ml of glacial acetic acid wasadded a warm solution of 7.5 g (0.0258 mole) of2-nitr0-5-[(p-chlorophenyl)thio]benzonitrile in 50 ml of glacial aceticacid. The stirred mixture was heated at 50 for 2 hr, stirred for 2 hr atroom temperature and then poured into 1 l. of ice-water containing 110ml of 50% sodium hydroxide. The crude product was collected, washed withwater and air-dried. Recrystallization from 70% aqueous ethanol(charcoai) gave 4.5 g (67%) of product, mp 123l25.

Anal. Caled for CmH ClNgSZ C. 59.88

Found: C. 59.82;

2,4-Diamino-6-[ (p-ehlorophenyl)thio]quinazoline,

one-third Hydrate.

A mixture of 4.5 g (0.0173 mole) of2-amino-5-[(pchlorophenyl)thio]-benzonitrile, 2.2g (0.019 mole) ofchloroformamidine hydrochloride and 10.5 ml of dry diglyme was heated to145 C. A brisk evolution of hydrogen chloride occurred producing a clearsolution which solidified rapidly. The mixture was maintained for 1 hrat 145, cooled and diluted with ether. The

Anal. Calcd for C H ClN S' H O: c.5445; H, 3.91;

Found: C. 54.53; H, 4.03;

N, 18.34. H O. 2.15.

EXAMPLE 11 Preparation of 2,4-Diamino-6-[ a,a,a-trifluoro-m-tolyl )thioquinazoline 2-Nitro-5-[(a,a,a-trifluoro-m-tolyl )thio lbenzonitrile wasprepared from m-trifluoromethylthiophenol and-chlor0-2-nitrobenzonitrile. Reduction with stannous chloride afforded2-amino-5-[(a,a,o:-trifluoro-mtolyl)thio]benzonitrile which wascondensed with chloroformamidine hydrochloride to give the desiredendproduct compound having the structure shown in FIG.

2-Nitro-5- a,a,a-trifluoro-m-tolyl )thio 1 benzonitrile A mixture of11.6 g (0.065 mole) of m-trifluoromethylthiophenol, 11.9 g (0.065 mole)of 5-chloro-2- nitrobenzonitrile and 10.0 g (0.072 mole) of anhydrouspotassium carbonate in 160 ml of acetone was stirred v under reflux for3 hr, cooled and filtered. The fitrate was concentrated to dryness andthe oily residue was triturated several times with hot iso-octane. Oncooling the residue solidified forming yellow crystals. The solid wasrecrystallized from anhydrous ethanol to give 15.3 g (72.5%) of thedesired product. mp 96-98.5.

Anal. Calcd for C H F N O S: C. 51.86; Found; C. 51.86;

2-Amino-5[ a,a,atrifluoro-m-tolyl )thio benzonitrile.

To a stirred solution of 34.4 g (0.153 mole) of stannous chloridedihydrate in a mixture of 50 ml of concentrated hydrochloric acid and 20ml of glacial acetic acid was added slowly a warm solution of 15. l g(0.0465 mole) of 2-nitro-5-[(a,a,cx-trifluoro-mtolyl)thio}benzonitrilein 50 ml of glacial acetic acid. The temperature was held below 25during the 1.5 hr addition period. After stirring at room temperaturefor 18 hr, the clear solution was poured slowly into 600 ml of ice watercontaining ml of 50% sodium hydroxide solution. The white solid whichprecipitated was collected and dried. The crude product was trituratedwith 250 ml of hot 95% ethanol and filtered. The filtrate wasconcentrated to ml and chilled. The white crystals which formed werecollected and dried to give 1 l .l g (81%) of the desired product, mp ll4l 16.

Anal. Calcd for C H F N Sz C, 57.13; H. 3.09; N. 9.52. Found. C, 56.97;H, 318; N. 9.34.

2,4-Diamino-6-[ cx,a,a-trifluoro-m-tolyl )thio lquinazoline A stirredmixture of 10.0 g (0.0371 mole) of 2- amino-5- a,a,a-trifluoro-m-tolyl)thio lbe nzonitrile and 4.7 g (0.0408 mole) of chloroformamidinehydrochloride in 20 ml of diglyme was placed in an oil bath at l50l55. Ahomogeneous solution soon formed. hydrogen chloride was evolved and thena new yellow solid began to precipitate. After 0.5 hr the mixture wascooled to room temperature and the solid was collected. washed firstwith diglyme and then with ethyl acetate and dried. The solid wasrecrystallized from 70% aqueous ethanol containing excess ammoniumhydroxide. After drying in vacuo 7.8 g (62.5%) of the desiredend-product. mp 229230.5 was obtained.

Anal. Calcd for C H F N S: C. 53.57; H. 3.31); N. 16.66. Found: C,53.58; H. 3.45; N, 16.83.

EXAMPLE 11] Preparation of 2,4-Diamino-6-( Z-naphthylthio )quinazoline2-Nitro-5-(Z-naphthylthio)benzonitrile was prepared from B-thionaphtholand 5-chloro-Z-nitrobenzonitrile. Reduction with stannous chlorideafforded 2-amino-5- (Z-naphthylthio)benzonitrile which was condensedwith chloroformamidine hydrochloride to give the desired end-producthaving the structure shown in FIG. 4.

2-Nitro-5-( 2-naphthylthio)benzonitrile A mixture of 20.5 g (0.128 mole)of B-thionaphthol. 24.5 g (0.134 mole) of 5-chloro-2-nitrobenzonitrileand 19.5 g (0.141 mole) of anhydrous potassium carbonate in 300 ml ofbenzene was stirred under reflux for 4 hr and filtered hot to remove thesalt. The benzene solution was concentrated and cooled. The brittleyellow solid which precipitated was collected and dried. Afterrecrystallization from acetonitrile 18.1 g (46%) of the desired product,mp 139141, was obtained.

Anal. Calcd for C H N O S: C, Found: C,

2-Amino-5-(2-naphthylthio)benzonitrile To a well stirred solution of14.8 g (0.066 mole) of stannous chloride dihydrate in a mixture of 40 mlof concentrated hydrochloric acid and ml of glacial acetic acid wasadded slowly a warm solution of 6.0 (0.02 mole) of2-nitro-5-(Z-naphthylthio)benzonitrile in 60 ml of glacial acetic acid.External cooling kept the temperature of the reaction mixture below 20 Cduring the addition. The resulting yellow suspension was stirred for 18hr at room temperature producing a white suspension which was pouredinto a stirred icewater mixture containing 110 ml of 50% sodiumhydroxide solution. The white solid which precipitated was collected,washed with water and dried. The crude product was treated with hot 95%ethanol, and filtered to remove the insoluble inorganic material. Thechilled filtrate yielded a white crystalline solid which was collectedand dried to give 3.3 g (59%) of the desired product, mp 140.5-142.5.

Anal. Calcd for C H N S: C, 73.88, H, 4.35; N, 10.14. Found: C, 74.05;H, 4.45; N, 10.18.

2,4-Diamino-6-(2-napthylthio)quinazoline with 7 ml of diglyme and thesolid was collected,

washed with ethyl acetate and dried. The solid was recrystallized oncefrom aqueous ethanol containing excess ammonium hydroxide and once fromanhydrous ethanol. After drying in vacuo (50) 1.4 g (38%) of the desiredproduct, mp 2265-2281 was obtained.

Anal. Calcd for C H N S: C,

67.90, H, 4. Found: C, 67.87; H, 4.

EXAMPLE IV Preparation of 2,4-Diamino-6-( Z-naphthylsulfinyl)quinazoline, one-eighth hydrate Brief treatment of2,4-diamino-6-(2-naphthylthio)- quinazoline (Example 111 above) inacetic acid with hydrogen peroxide afforded the desired end-productcompound having the structure shown in FIG. 5.

2,4-Diamino-6-(Z-naphthylsulfinyl)quinazoline, one-eighth hydrate To astirred suspension of 1.59 g (0.005 mole) of 2,4-diamino-6-(2-naphthylthio)quinazoline in 32 ml of glacial acetic acidwas added 13.0 ml (0.13 mole) of 30% hydrogen peroxide solution. Themixture was allowed to stir at room temperature until a clear solutionformed 0.50.75 hr). The solution was then poured into a stirredice-water mixture containing 28.5 ml of 50% aqueous sodium hydroxide.The white solid which precipitated was collected, washed with water anddried in vacuo (50). The solid was reprecipitated twice fromdimethylformamide with water and dried in vacuo (50) to give 1.2 g(71.5%) of the desired end-product compound, mp 312314 with preliminarysoftening.

Anal. Calcd for C H N OS'1/8H O: C, 64.22; H, 4.24; N, 16.65; H O, 0.67.

Found: C, 64.22; H, 4.26;

EXAMPLE V Preparation of 2,4-Diamino-6-( 2-naphthylsulfonyl)quinazoline,0.9

hydrate Oxidation of quinazoline (Example 111 above) in acetic acid withaqueous hydrogen peroxide gave the desired endproduct compound havingthe structure shown in FIG. 6.

2,4-Diamino-6-( 2-naphthylsu1fonyl )quinazoline, 0.9 hydrate To astirred suspension of 1.59 g (0.005 mole) of 2,4-diamino-6-(2-naphthylthio)quinazoline in 25 ml of glacial acetic acidwas added ml (0.13 mole) of 30% hydrogen peroxide solution. The mixturewas stirred at room temperature for 23 hr. The pale yellow solution waspoured slowly into a stirred ice-water mixture containing 24 m1 of 50%aqueous sodium hydroxide. The prepcipitate which formed was collectedand washed with water. The sticky white solid was suspended in 200 ml ofhot absolute ethanol. The mixture was cooled and the solid was collectedand dried in vacuo (50) to give 1.6 g (91.5%) of the desired end-productcompound, mp 310.

2,4-diamino-6-( 2-naphthylthio Anal. Calcd for C H N O S09H O: C. 58.97;H, 4.31

N, 15.29; H O, 4.42.

Found: C, 58.91; H, 4.13;

N, 15.40; H O, 4.40.

The infrared spectrum revealed new absorption at 1 155 cm and at 131 1cm to confirm the presence of S ANTIMALARIAL UT1 LlTY The five newcompounds prepared in the above examples show unexpectedly highantimalarial activity. This fact can be seen in Table l which gives theresults of antimalarial evaluations against Plasnwdr'um berghei in miceand Plasmodium gallinaceum in chicks.

This test system is based on comparisons of response to test compoundsby Plasmodium berghei malaria in mice as expressed in maximum survivaltimes as compared to survival times of untreated control mice. Thus,compounds noted as active produce increases in the survival times of thetreated mice that are significant when compared with the survival timesof the untreated control mice. Since an established disease is lesssensi tive to treatment than a disease in the early stages ofdevelopment, treatment is withheld until the parasitemia is relativelyhigh in order to insure a more reliable assay of activity and theselection of appropriate compounds for intensive preclinical studies.

Utilizing young lCR/HA Swiss mice and a standard inoculum of Plasmodiumberghei, it is possible to produce a uniform disease fatal to 100% ofuntreated animals within 6 to 8 days with a mean survival time of 6.2

days.

test are approximately of the same age. Animals on test are house inmetal-topped plastic cages, given a standard laboratory diet and waterad lib.

Test animals receive an intraperitoneal injection of 0.5 ml. of a 1:100dilution of heparinized hearts blood with a minimum of 90% parasitizedcells drawn from donor mice infected 1 week earlier with Plasmodiumberghei. The donor strain is maintained by weekly passages in separategroups of mice inoculated with a 0.5 ml. of 1:500 dilution ofheparinized hearts blood.

Test compounds are usually administered after solution or suspension insesame or peanut oil. A single dose is given subcutaneously 72 hoursafter the mice are infected with Plasmodium berghei. At this time a10-15% parasitemia has developed; the disease is well established buthas not produced sufficient debility to alter the response of the hostto toxic effects of the drug on test. Since treatment is withheld forthree days to permit the infection to become well established and deathoccurs in untreated controls within 6 to 8 days, it is felt that thissystem prevents a candidate compound with the maximum challenge. Treatedanimals are kept under observation for days. Survivors at the end ofthis period of time are considered as cured. In order to check factorssuch as changes in the infectivity of Plasmodium berghei or in thesusceptibility of the host or to detect technical errors a group ofinfected animals treated with pyrimethamine at dose levels producingdefinite increases in survival time is included as a positive control inevery experiment. In each experiment test compounds are administered ingraded dosages. With highly active compounds, increases in dose levelsare usually followed by increases in the survival time of the treatedmice. However, if an active drug is toxic for the host, its toxicity maybecome a limiting factor; continued increases in dose levels alsoincrease the toxic effects and may result in the diminution of survivaltimes. Deaths prior to the sixth day, when untreated controls begin todie, are regarded as non parasitic and become the basis for toxicityevaluations.

Table 1 Antimalarial Evaluation Against Plasmodium berghei in Mice andPlasmodium gallinat'eum in Chicks Com ound (Ex amp e No. and FigureShowing P. bergher' Sm 1e Subcutaneous dose KfiS 1; C after mglhgz 1?.allinaceum Single 5. c. dose Structure) 640 320 160 40 20 10 5 2 5 1.25mg/kg AMST;C

C5 C5 C5 258 13.1;C2 9.2 10.1 6.8 3.6 1.7 320 C5 1 (FIG. 2) C5 C5 :C413.1;C2 11.1 10.1 6.8 2.5 1.7 22.2;C2

141-,C4 E11 80 16.7 15.8;C4

C5 C5 C5 C5 14.9;C3 12.7 9.1 8.7 2.7 0.5 160 15.4 11 (F16 3) C5 C5 C515.9;C3 13.1 9.3

C4 (5 C5 C5 C5 C5 C5 11 1 6 5 5.3 2 9 320 16.0;

C5 C5 C5 C5 C5 11.3 160 15.0;C4 111 (FIG. 4) C5 C5 80 16.2 40 12.4 207.8 10 6.2

C5 C5 C5 C5 C5 C5 C5 142 10.9 6 7 1V (FIG. 5) C5 C5 C5 C5 C5 31.9 ,C2

C5 C5 ;C4

C5 C5 C5 C5 C5 C5 C5 15.6;C2 12 1 10.9 40 16.4 C5 C5 C5 C5 C5 C5 9.9;C45.9 4.5 20 11.0 V (FIG. 6) C5 C5 C5 10 9.0 5 7.8 2.5 4.8 1.25 2.0

"AMS'l' is the mean survival time (days) of treated mice tMSll') minusthe mean survival time (days) of control mice from 6.1 to (1.5 days. Lindicates the number 01' mice surviving at 60 days post infection andtermed "cured";

sub-inoculation is unavailable.

'AMS'l' is the mean survival time (days) of treated chick MSl'l) minusthe mean survival time (days) f Cmttrol chicks t MSTC 1. 1n the presentstudy the MS'l'C ranged from 3.0 to 4.0 days. C designates the number01' chic s surviving to 30 days post infection and termed "cured"; datato establish parasitological care based on sub-inoculation isunavailable. Each entry at each dose level represents results with a 5animal group.

[MSTC 1. 1n the present study the MSTC ranged data to cstahlishparasitnlogical cure based on Two compounds were also tested for theiroral suppressive antimalarial effects against another normaldrug-sensitive strain of Plasmodium berghei (KEG-173) in mice utilizingpublished test procedures [P. E. Thompson et al., Exp. Parasitol, 25:32(1969)]. The SD (the daily dose in mg/kg of body weight required for 90%suppression of the parasitemia in treated mice relative to control mice)for the compound 2,4- diamino-6- I p-chlorophenyl )thio ]quinazoline(Example I: FIG. 2) is 0.22 mg/kg/day as estimated graphically usingsemi-logarithmic paper. The SD for the compound2,4-diamino-6-(2-naphthylio)quinazoline (Example III, FIG. 4) is 0.085mg/kg/day as estimated graphically. The quinine equivalent Q (the ratioof the SD of quinine hydrochloride 74.5 mg base/kg/day to the SD of thetest compound under comparable conditions) for the compound of Example I(FIG. 2) is 338 and the Q of the compound of Example III (FIG.'

It has been established that the New World monkey, Aotus'trivirgatus(also known as douracouli, owl monkey or night monkey) is especiallysusceptible to the parasites of human malaria when splenectomized orgiven immune-suppressant agents. Monkeys so prepared were first used indeveloping laboratory models for human Plasmodium vivax [M. D. Young, J.A. Forter, Jr., and C. M. Johnson, Science, 153, 1006 (1966); J. A.Porter, Jr., and M. D. Young, Military Med, 131, supplement, 952 (1966);D. C. Baerg, J. A. Porter, Jr., and M. D. Young, Amer. J. Trop. Med.Hyg., 18. 346 (1969); D. C. Baerg and M. D. Young, Military Med., 134,special issue, 772 (1969)] and for Plasmodiumfalciparum [Q. M. Geimanand M. J. Meagher, Nature, 215, 437 (1967); Q. M. Geiman, W. A.Siddiqui, and

(1969); P. G. Contaeos and W. E. Collins, Science. 161, 56 (1968)]. Inparticular, such work has constituted a noteworthy advance inmalariology in the latter instance, for there are numerous strains ofmalignant tertain malaria which pose marked medical problems because thestrains are resistant to most antimalarial drugs now available. Earlier,Old World monkeys infected with simian malaria parasites had been foundto be valuable for laboratory models of malarias [ef., W. Peters,Chemotherapy and Drug Resistance in Malaria. Academic Press. Inc.. NewYork. 1970]. Through detailed study of aspects of such infections [cf..G. R. Coatney, W. E. Collins, McW. Warren, and P. G. Contacos, ThePrimate Malarias, US. Government Printing Office. 1972], a reproducibleand standardized system for the testing of chemotherapeutic agentsagainst several strains of Plasnwdium falciparum in intactAotustrivirgatus has been developed [L. H. Schmidt, Bulletin of SouthernResearch Institute, vol. 24, no. 1, page 9 J. V. Scheel, Military Med.,134, special issue, 780

The standardized Aotus test system (Schmidt, loc. cit.) has rendered itpossible to determine the efficacy of antimalarials under circumstancesakin to those in clinical cases of falciparum malaria. This significantadvance eliminated the potential of hazards to man through use ofvolunteers to evaluate candidate drugs against strains ofPlasmodiumfalciparum following successful trials in malarialinfections-of lesser creatures. Response in the secondary test systemhas closely paralleled those shown in man by antimalarials. Thisprovides firm basis for development of antimalarial agents which aresafe and more broadly effective than those now in use, and which may betaken into the clinic with greater assurances of success than hitherto.

Tables 2 and 3 give the results of the antimalarial evaluation using theAotus test system.

Table 2 Antimalarial Evaluation Using the Aotus Test System with theChloroquine-Susceptible Malayan Camp-CH/Q and Chloroquine-ResistantVietnam Oak Knoll Strains of Plasmudium falciparum Daily Response toTreatment use No. Suppressed/No. No. Parasite Clearances/ No. Cures lNo.Mg/kg Infected with Strain No. Infected with Strain Infected with StrainBody Malayan Vietnam Malayan Vietnam Malayan Vietnam Compound WeightCamp-CH/Q Oak Knoll Camp-CH/O Oak Knoll Camp CH/Q Oak Knoll Examplcl0.31 0/2 3/3 0/2 3/3 0/2 3/3 (FIG. 2) 1.25 3/3 3/3 3/3 3/3 0/2 3/3 5.03/3 3/3 3/3 3/3 3/3 3/3 0.19 0/2 2/2 0/ 2 2/2 0/2 0/2 0.78 5/5 5/5 l/55/5 0/5 2/5 Example III 1.56 3/3 3/3 2/3 3/3 0/3 3/3 (FIG. 4) 3.125 6/66/6 6/6 6/6 4/6 5/5 6.25 3/3 3/3 3/3 3/3 3/3 3/3 12.5 2/2 l/l 2/2 l/l2/2 l/l 50.0, 2/2 l/l 2/2 I/l 2/2 1/1 0.025 3/3 6/6 0/3 3/6 0/3 0/40.098 3/3 6/6 l/3 6/6 0/3 1/3 0.19 2/2 2/2 2/2 2/2 1/2 l/2 Example IV0.39 6/6 7/7 6/6 7/7 2/5 5/5 (FIG. 5) 0.78 5/5 5/5 5/5 S/5 4/5 5/5 1.566/6 6/6 6/6 6/6 5/6 6/6 3.125 3/3 6/6 3/3 6/6 2/2 5/5 12.5 2/2 2/2 2/22/2 2/2 2/2 50.0 III III III III I/l l/l 0.025 0/3 4/4 0/3 4/4 2/3 2/3Example V 0.098 3/3 4/4 0/3 4/4 0/3 2/2 (FIG 6) 0.39 6/6 8/8 6/6 8/8 5/66/6 1.56 0/6 9/9 6/6 9/9 6/6 6/6 6.25 3/3 3/3 3/3 3/3 3/3 /3 Table 3SUMMARY OF COMPARATIVE ACTIVITIES OF THE COMPOUNDS OF EXAMPLE IV (FIG.5) AND EXAMPLE V (FIG. 6) AGAINST ESTABLISHED INFECTIONS WITH THECHLOROQL'INE SUSCEPTIBLE MALAYAN CAMP ZH/O AND CHLOROOUINF RESISTANTVIETNAM MONTEREY STRAINS OF PLASMUDIUM FALCJPARUM Daily Responses ofInfections Dose No. No. Cures/No, Infected Parasites Clearances/No.Infected Strain Mg/Kg Thera eutic A ent Therapeutic Agent Body WtCompound of Example 1 Compound of Example V Compound ot Example lVCompound of EXumpIc V X 7 (FIG. 5) (F106) (FIG. 5) (FIG. 6)

Malayan 0.00625 -Camp- 00125 /2 0/2 Cl'l/Q 0.025 3/6 0/6 0/6 0/6 0.0492/5 0/7 0/4 0/7 0.098 7/9 3/12 4/9 U12 0196 5/7 6/11 7 4/11 0.39 /913/15 6/9 10/13 0.78 7/7 2/2 4/7 2/2 1.56 12/12 9/10 11/12 9/10 3.1258/8 1/1 7/7 l/l Vietnam 0.00625 0/1 0/1 Oak 0.0125 Knoll 0.025 3/6 /90/6 7/9 0.049 4/4 0/1 1/4 0/1 0.098 6/6 11/11 3/6 10/11 0.196 2/3 1/30139 7/7 11111 7/7 ll/ll 0.78 5/5 5/5 ANTIBACTERIAL UTILITY Three of thecompound prepared in the above examples show antibacterial utility asdemonstrated by the evaluation results shown in Table 4.

Table 4 Compound (Example No. and Figure Showing Structure)Antibacterial Evaluation Inhibitory drug concentration, ug/ml" Siretucocc'us Slaphy/woccus Slaphylococcus Escherichia S/uge/la j ecalisaurcus aureus cu/i summ' MGH-2 UC-76 518713 Vogcl C l 0 I FIG. 2 0.250.25 0.25 1.0 5.0 Ill FIG. 4 0.25 O.25 0.25 0.25 lV FIG. 5 0.25 0.250.25 0.25

"Grandient plate in vitro antibacterial test employed.

ications at several dose levels has been tabulated, with 1 claim:

indications given from suppression of signs and symptoms andparasitological status to cures of the malaria infections. All of thenovel compounds produced satisfactory response in the infections causedby either chloroquine-sensitive or chloroquine-resistant strains ofparasites. Remarkably, there was even suggestion that those of thelatter type responded somewhat better than the former. The mosteffective compounds were found to be 2,4-diamino-6-(Z-naphthylsulfinyl)-quinazoline (FIG. 5) and 2,4-diarnino-6-(2-naphthylsulfonyl)quinazo1ine(FIG. 6). More detailed study of the profiles of potency for those twowas indicated, and results thereof have been summarized in Table 3. Onthe basis of the fact that 2,4-diamino-6-(Z-naphthylsulfonyl)quinazoline had the greater levels of effectivenessagainst chloroquine-resistant Plasmoa'ium falciparum (Vietnam Oak KnollStrain), that compound has been considered to be the best representativeof the present series.

l. A compound having the structural formula N OYNII: A r-Y wherein Y isS, SO, or S0 and Ar is p-chlorophenyl,

a,a,a-trifluoro-m-tolyl, or Z-naphthyl.

2. 2,4-diamino-6-I p-chlorophenyl )thio lquinazoline.

3. 2,4-diamino-6-[ (a,0z,o:-trifluoro-m-tolyl )thio 1- quinazoline.

4. 2,4-diamino-6-( Z-naphthylthio )quinazoline. 5. 2,4diamino-6-(Z-naphthylsulfinyl )quinazoline. 6. 2,4-diamino-6-( 2-naphthylsulfonyl)quinazoline. =l=

1. A COMPOUND HAVING THE STRUCTURAL FORMULA 2.2,4-diamino-6-((p-chlorophenyl)thio)quinazoline.
 3. 2,4-diamino-6-((Alpha , Alpha , Alpha -trifluoro-m-tolyl)thio)quinazoline. 4.2,4-diamino-6-(2-naphthylthio)quinazoline. 5.2,4-diamino-6-(2-naphthylsulfinyl)quinazoline. 6.2,4-diamino-6-(2-naphthylsulfonyl)quinazoline.